Summary The Chemical Biology and Therapeutics Innovation Core (Core D) referred in the PP text as ?Therapeutics Core? will provide services to the four projects of this Program Project and work collaboratively with several project leaders to accomplish the innovation component. The long-term goal of this core is to provide support for the needs of the individual projects on synthesizing currently available novel autophagy modulators, validating compounds from screening and hit-to-lead medicinal chemistry optimization targeting different autophagy pathways and assessing the impact of these compounds by modulating autophagy in Alzheimer?s disease and Alzheimer?s disease-related dementias. The specific aims of this core are: 1) to provide a chemical biology facility that will assist the investigators of the program projects and cores to have access to novel modulators of autophagy and information for their proper formulation and use in cellular and in vivo mouse studies. 2) to facilitate chemical screening approaches, hit selection, hit validation, and target identification and engagement using chemical biology approaches 3) to work with project leaders for the validation and expansion of hit compounds and hit-to-lead optimization using principles of medicinal chemistry. Components: 1) The chemical biology unit will provide chemical synthesis of compounds and chemical probes, compound distribution, analytical characterization of compounds and assistance with the solubilization, formulation and assay of compounds 2) The innovation unit will validate, optimize and implement different chemical modulators of autophagy using medicinal chemistry towards proof-of-concept in vivo studies for Alzheimer?s disease and Alzheimer?s disease-related dementias. Services: the core will assist with the design, chemical synthesis, purification and analytical characterization of novel autophagy modulators, the design and synthesis of chemical probes for target identification and engagement studies in vivo, validation of hits and hit expansion studies by computational drug design approaches, design and synthesis of focused chemical libraries for structure-activity relationships studies, medicinal chemistry for hit-to-lead optimization, advice and assistance with solubilization, proper use in assays, pharmacokinetic studies, and formulation procedures for evaluation of compounds in vivo. Relevance: This core is essential for the translational efforts of this PP to develop pre-clinical proof-of-concept on the validity of targeting autophagy as an effective intervention to prevent or delay onset of Alzheimer?s disease pathology. We anticipate that lead molecules generated and tested with the core could set the basis for future development clinical drugs for this devastating age-related disorder.